Adult T-cell progenitors retain myeloid potential

During haematopoiesis, pluripotent haematopoietic stem cells are sequentially restricted to give rise to a variety of lineage-committed progenitors. The classical model of haematopoiesis postulates that, in the first step of differentiation, the stem cell generates common myelo-erythroid progenitors and common lymphoid progenitors (CLPs). However, our previous studies in fetal mice showed that myeloid potential persists even as the lineage branches segregate towards T and B cells. We therefore proposed the 'myeloid-based' model of haematopoiesis, in which the stem cell initially generates common myelo-erythroid progenitors and common myelo-lymphoid progenitors. T-cell and B-cell progenitors subsequently arise from common myelo-lymphoid progenitors through myeloid-T and myeloid-B stages, respectively. However, it has been unclear whether this myeloid-based model is also valid for adult haematopoiesis. Here we provide clonal evidence that the early cell populations in the adult thymus contain progenitors that have lost the potential to generate B cells but retain substantial macrophage potential as well as T-cell, natural killer (NK)-cell and dendritic-cell potential. We also show that such T-cell progenitors can give rise to macrophages in the thymic environment in vivo. Our findings argue against the classical dichotomy model in which T cells are derived from CLPs; instead, they support the validity of the myeloid-based model for both adult and fetal haematopoiesis.     

低温及应变率对矿用圆环链冲击性能的影响

为了了解回采工作面刮板输送机圆环链在卡链状态下力学性能,文中利用ANSYS/LS-DYNA软件,对含有V型缺口圆环链进行数值模拟冲击实验分析,特别是就低温和应变率等因素对圆环链冲击性能的影响进行了比较详细的研究和讨论.研究结果表明温度降低会导致矿用受冲击圆环链破断时吸收能量减小和缩短初始破断时间,另外,应变率(加载速率)也会使破断应力增大和缩短初始破断时间.     

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.     

枯草芽孢杆菌生产鸟苷的途径分析

利用途径分析的方法对枯草芽孢杆菌发酵生产鸟苷的途径进行分析,确定了3个基本反应模型,计算出最优途径的理论产量和通量分布．三个基本模型的理论摩尔产量分别为0．625、0．75、0．667．通过调整化学调节因子NH4^ 和Mg^2 ,可以使鸟苷产量由14．4g／L提高到19．2g／L。     

Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS

Cellular and Molecular Life Sciences - Transactive response DNA-binding protein 43 kDa (TDP-43) encoded by the TARDBP gene is an evolutionarily conserved heterogeneous nuclear...     

桂林大阪两市新生儿脐带血和母乳中脂溶性维生素浓度比较

为探讨婴儿佝偻病及新生儿出血症与微量营养素水平的关系，对桂林市哺乳妇女及新生儿脐带血进行了脂溶性维生素Ａ、Ｄ、Ｅ、Ｋ的测定，并与日本国大阪市哺乳妇女及新生儿作了对照比较。结果表明：脐带血和母乳中的维生素Ａ和Ｅ浓度在中日两国间无显著性差异。脐带血中的维生素Ｄ也无差异。但桂林市新生儿脐带血中β－胡萝卜素及玉米黄质显著低于日本大阪市新生儿，而ＰＩＶＫＡ－２值却明显升高，提示桂林市孕妇黄绿色蔬菜及水果的摄     

TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity

The presenilin proteins (PS1 and PS2) and their interacting partners nicastrin, aph-1 (refs 4, 5) and pen-2 (ref. 5) form a series of high-molecular-mass, membrane-bound protein complexes that are necessary for gamma-secretase and epsilon-secretase cleavage of selected type 1 transmembrane proteins, including the amyloid precursor protein, Notch and cadherins. Modest cleavage activity can be generated by reconstituting these four proteins in yeast and Spodoptera frugiperda (sf9) cells. However, a critical but unanswered question about the biology of the presenilin complexes is how their activity is modulated in terms of substrate specificity and/or relative activities at the gamma and epsilon sites. A corollary to this question is whether additional proteins in the presenilin complexes might subsume these putative regulatory functions. The hypothesis that additional proteins might exist in the presenilin complexes is supported by the fact that enzymatically active complexes have a mass that is much greater than predicted for a 1:1:1:1 stoichiometric complex (at least 650 kDa observed, compared with about 220 kDa predicted). To address these questions we undertook a search for presenilin-interacting proteins that differentially affected gamma- and epsilon-site cleavage events. Here we report that TMP21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage without affecting epsilon-secretase activity.     

Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.     

Spatially resolved observation of crystal-face-dependent catalysis by single turnover counting

Catalytic processes on surfaces have long been studied by probing model reactions on single-crystal metal surfaces under high vacuum conditions. Yet the vast majority of industrial heterogeneous catalysis occurs at ambient or elevated pressures using complex materials with crystal faces, edges and defects differing in their catalytic activity. Clearly, if new or improved catalysts are to be rationally designed, we require quantitative correlations between surface features and catalytic activity--ideally obtained under realistic reaction conditions. Transmission electron microscopy and scanning tunnelling microscopy have allowed in situ characterization of catalyst surfaces with atomic resolution, but are limited by the need for low-pressure conditions and conductive surfaces, respectively. Sum frequency generation spectroscopy can identify vibrations of adsorbed reactants and products in both gaseous and condensed phases, but so far lacks sensitivity down to the single molecule level. Here we adapt real-time monitoring of the chemical transformation of individual organic molecules by fluorescence microscopy to monitor reactions catalysed by crystals of a layered double hydroxide immersed in reagent solution. By using a wide field microscope, we are able to map the spatial distribution of catalytic activity over the entire crystal by counting single turnover events. We find that ester hydrolysis proceeds on the lateral {1010} crystal faces, while transesterification occurs on the entire outer crystal surface. Because the method operates at ambient temperature and pressure and in a condensed phase, it can be applied to the growing number of liquid-phase industrial organic transformations to localize catalytic activity on and in inorganic solids. An exciting opportunity is the use of probe molecules with different size and functionality, which should provide insight into shape-selective or structure-sensitive catalysis and thus help with the rational design of new or more productive heterogeneous catalysts.